TW593307B - Sulfonamide-substituted benzopyran derivatives, processes for their preparation, their use as a medicament, and pharmaceutical preparations comprising them - Google Patents

Abstract

Compounds of the formula I having the meanings of the substituents indicated in the claims are outstandingly active substances for the production of medicaments for the prophylaxis and for the therapy of cardiovascular disorders, in particular arrhythmias, for the treatment of ulcers of the gastrointestinal region or for the treatment of diarrheal diseases.

Description

593307 A7 B7 V. INSTRUCTIONS (1) The present invention relates to a compound of formula I ο 〇 R(4( \χ// Ri3, Ν

R(6) R(2) R(1) wherein R(l), R(2), R(3), R(4), R(5), R(6) and B are as defined below, and related to the preparation method thereof and its use, Especially refers to the use of medicine. These compounds affect the potassium channel opened by cyclic adenosine monophosphate (CAMP) or affect the Iks channel, and are highly suitable for pharmaceutically active compounds, for example: for the prevention and treatment of cardiovascular diseases (especially arrhythmia), for the treatment of gastrointestinal The site is ulcerated or treats the disease. In the field of medicinal chemistry, 4-meramine-based chroman derivatives have been actively studied in recent years, and the most representative of these derivatives is Cromakalim of formula A (J. Med. Chem. 1986, 29, 2194). (Please read the notes on the back and fill out this page) • A clothing·

, 1T Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives, Printing

OH5\CH3 This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 87397A (9HOEDEU) Ministry of Economic Affairs Central Bureau of Standards Staff Consumer Cooperatives Printed 593307 A7 B7 Five 7# Ming Description (2) _ Ke Makarin And other related 4-branched amines are compounds that have a relaxing effect on smooth muscle organs, so they can be used to relax the muscle of the jir tube to lower blood pressure, and to treat asthma by relaxing the smooth muscle of the airway. All of these agents typically act at the cellular level, such as smooth muscle cells, thus opening a specific K+ channel that is sensitive to ATP. The phenomenon that the negative charge rate (hyperpolarization) of the cells induced by K+ efflux will be countered by the increase in intracellular Ca2+ concentration via the secondary machine, and thus the cell activation results in, for example, muscle contraction. The compounds of the formula I according to the invention differ structurally from these guanamine derivatives, in particular by the sulfonamide functional groups. Although clemaline (formula A) and similar guanamine-based compounds act as openers for ATp-sensitive K+ channels, compounds of formula I according to the invention having a sulfonamide structure are not K+ (ATP) The channel exhibits any open action, but surprisingly exhibits a strong and specific blockade (blocking) effect on the K+ channel, which is opened by cyclic adenosine monophosphate (cAMp) and essentially corresponds to K+ above. The (ATP) channel is different. More recent studies have shown that this K+ (cAMp) channel identified in colon tissue is very similar to, or even identical to, the Iks channel defined in the heart tissue. In fact, the compound according to the invention is applied to the guinea pig myocardium. The k-channel in the cells and the Iks channel expressed in Xenopus egg cells show a strong blocking effect. Thus, this blocking effect on the KlcAMP) channel or the Iks channel allows for the pharmaceutical action of the compounds according to the invention to be highly medically useful in vivo. _________4_ This paper size is suitable for the product (CNS) (210X297^JT"--------- (please read the note on the back and fill out this page again) 'Order_ Printed by the Central Bureau of Standards and Staff of the Ministry of Economic Affairs 593307 A7 ______ B7 V. INSTRUCTIONS (3) In addition to the above-mentioned clemaline and guanidine-based full-color derivatives, compounds having a 4-anthracene-based chroman structure are described in the literature. EP-A-389861 and JP01294677 3-hydroxychroman and chromene derivatives (e.g., Compound B) having a cyclic 4-sulfonamide group, respectively, which are said to utilize the activation of the K+ (ATP) channel as an antihypertensive agent. The patent application scope of the above-mentioned EP-A-389 861 also includes a compound having an acyclic 4-sulfonylamino group which is similar to the compound of the present invention, but the definition of R (5) is different. It has been surprisingly found, in particular Substituents for R(5) as described in this application, especially an alkane group, for example, butoxy or 4,4,4-trifluorobutoxy, having the same as in EP-A-389861 The compound of the column group provides a greater advantage, especially in blocking the effectiveness of the ks channel. EP-A-389861 Such similar compounds that apply for exclusive rights but do not provide examples support also have utility for the iks channel, but this effect is less significant and has not been appreciated by the author of the application. Even if the author has specifically addressed it For the use of arrhythmia, the compound claims to open the K+ (ATP) channel, but the repolarization time should be shortened by opening the channel, thus having a anterior arrhythmia effect. In this paper, Lu Xi should be mentioned. Lucchesi) et al. (J. Cardiovasc. Pharmacol 15, 15, 452), which shows in an impressive way that K+ (ATP) channel openers are not resistant to hypoxic heart or sudden anemia. The heart rhythm is not correct, but there will be life-threatening pre-fibrillation effects. This paper scale applies to the Chinese National Standard (CNS) A4 specification (-If (please read the back note first and then fill out this page). WI. 593307 i_____ Ministry of Economic Affairs Central Bureau of Standards Staff Consumer Cooperatives Printed A7 B7 Invention Notes (4) N"

In addition to the above compounds having a 4-sulfonamide-based color-filled structure, some other compounds are known, but they are structurally and biologically distinct from the compounds of the formula I according to the present invention. The chroman-compounds having a 4-phenylindoleamine structure have anti-embolism and anti-allergic properties as described in EP-A-315009. EP-A-370901 describes a 3- and a base color full and dilute derivative having a 4-anhydrous amine group on the CNS, wherein the remaining electricity price of nitrogen carries a hydrogen atom. Other 4-anthracene-based chroman derivatives are described in Bi〇〇rg, Med. Chem. Lett, 4 (1994), 769-773: "N-sulfonamides of benzopyran-related potassium channel openers (N-sulfonamides of benzopyran-related potassium channel openers: conversion of glybury de insensitive smooth muscle relaxants to potent smooth muscle contractors), and FEBS Letters 396 (N-sulfonamides of benzopyran-related potassium channel openers: conversion of glybury de insensitive smooth muscle relaxants to potent smooth muscle contractors) 1996), 271-275 "Special blockade of slowly activating Iks -6- (Specific blockade of slowly activating Iks -6- This paper scale applies Chinese National Standard (CNS) A4 specification (210X297 () Please read the notes on the back and fill out this page.) 593307 A7 B7 V. Inventions (5) channels by chromanols···) and pfhigers Arch.-Eur· J· Physiol· 429 (1995) 517- 530 : "The new inhibitor of Cl secretion by cAMp in the colon of the rabbit" acts to reduce the activation of KAMP mediated Cl-secretion in rabbit colon, acting by the reduction of cAMP- Activated K+ conductance) o The present invention relates to a compound of formula I. 〇, 〇 _ A〆〆 R (3, \ s a κ (sentence ν" ^

(Please read the note on the back and fill out this page.) .β. The Ministry of Economic Affairs, the Central Bureau of the Bureau of Employment, the Consumer Cooperative, prints R(6) R(2)' R(1) where R(5) is attached as 5, 6, Positions 7 and 8, wherein: R(1) and R(2) are hydrogen, CF3, C2F5, C3F7, an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, or a phenyl group, Unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, N02, CN, NH2, OH, methyl, ethyl, decyloxy, decylamine, amine Sulfonyl, sulfonyl, and sulfonylamino; or R(1) and R(2) The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 593307 A7 B7 V. Description of invention (6) Commonly an alkyl chain having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; R(3) is R(10)_CnH2n-NR(ll) or R( 10)-CnH2n- wherein a 0112 group in the CnH2n group can be replaced by -Ο-, -CO-, -S-, -so-, -S〇2_ or -NR(12a)-; R(12a) Is hydrogen, fluorenyl or ethyl; · R(l〇) is hydrogen, fluorenyl, cycloalkyl having 3, 4, 5, 6, 7, or 8 carbon atoms, CF3, C2F5, C3F7; η is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R(ll) is hydrogen or has 1, 2, 3, 4, 5 or 6 carbon atoms. Or; R(10) and R(ll) If η is not less than 3, they are jointly a bond; or R(3) and R(4) Printed by the Central Bureau of Standards Staff Consumer Cooperative of the Ministry of Economic Affairs (please read first) Precautions on the back side. Fill in this page together. It is an alkyl chain having 3, 4, 5, 6, 7 or 8 carbon atoms; wherein a CH2 group in the alkyl chain can be -0-, -CO -, S-, -SO-, -S〇2- or -NR(12a)-substitution: R(12a) is hydrogen, fluorenyl or ethyl; R(4) is R(13)-CrH2r, where QHh One of the groups (3112 group can be used by -0-, this paper scale applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 593307 A7 B7 V. Invention description (Please read the back note first and then fill in This page) -CH=CH_, -C^C_, -CO-, -C0_0_, _0_C0-, -S_, -SO-, -S02- or -NR(14)_ permutation; R(14) is hydrogen or has An alkyl group of 丨, 2 or 3 carbon atoms; R(13) is CH3, CF3, c2F5, C3F7, a cycloalkyl group having 3, 4, 5, 6, 7 or 8 carbon atoms, nr(15)R (16), phenyl or a nitrogen-containing heterocyclic ring having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein the phenyl group and the nitrogen-containing heterocyclic ring are unsubstituted or have 1 or 2 substituents selected from the group consisting of Substitution: F, Cl, Br, I, CF3, N02, CN, NH2, OH, methyl, ethyl, decyloxy, decylamino, sulfonyl, methanesulfonyl and methylamine R(15) and R(16) together are a chain of 4 or 5 methylene groups, one of which may be -〇-, -S-, -NH-, -N-(indenyl) or - N-(benzyl) substitution; printed by the Central Bureau of Standards Bureau of the Ministry of Economic Affairs, employee consumption cooperatives, is zero, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 15, 16, 17, 18, 19 or 20; R(5) is -Y-CsH2s-R(18) or phenyl; which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of: a, Br, I, CF3, N02, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfonyl, methanesulfonyl and vermiculite; -9 - This paper scale applies to China National Standard (CNS) A4 specification (21〇><297 mm) Printed by the Central Bureau of Standards and Staff Consumer Cooperative of the Ministry of Economic Affairs 593307 A7 _ B7_____ , invention description (8) Y is -0-, _S_ or -NR(IOC)-; R (l〇C) is hydrogen or an alkyl group having 1, 2 or 3 carbon atoms; S is 1, 2 3, 4, 5, 6, 7, or 8; R(18) is hydrogen, CF3, C2F5, C3F7, a cycloalkyl group having 3, 4, 5, 6, 7, or 8 carbon atoms, _C00R(21) And NR(15a)R(16a), an unsubstituted nitrogen-containing heterocyclic ring having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, a phenyl group or a thiophenyl group, wherein the phenyl group is The thienyl group is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, decyl, methoxy, sulfonyl, methanesulfonyl and methanesulfonate. Amine; R(15a) and R(16a) together are chains containing 4 or 5 methylene groups, one of which can be -〇_, -S-, -NH-, _N-(methyl) Or -N-(benzyl) substitution; R(21) is hydrogen or a burnt group having 1, 2 or 3 carbon atoms; R(6) is OR(l〇d) or OCOR(lOd); R(l 〇d) is hydrogen or a burnt group having 1, 2 or 3 carbon atoms; B is hydrogen; or R (6) is a bond with B; -10- This paper scale applies to China & A4 specification (210X297 mm^---" (Please read the back first Note to fill out this page)

Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs 593307 A7 B7 V. INSTRUCTIONS (9) and its physiologically tolerable salts. Preferred are compounds of formula I, wherein R(l) and R(2) are respectively hydrazine, CF3, C2F5, C3F7 or an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms; or R ( l) together with R(2) is a stretching bond having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; R(3) is R(10)-CnH2n; R( 10) is methyl, CF3, C2F5, C3F7; η is 0, 1, 2, 3, 4, 5 or 6; R(4) is R(13)-CrH2r where (CH2* in a ^^2ι• group) The group can be -Ο-, -CH=CH-, -C tri-C-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -S〇2_ or NR (14) Substitution; R(14) is hydrogen or a burnt group having 1, 2 or 3 carbon atoms; R(13) is CH3, CF3, C2F5, C3F7, having 3, 4, 5, 6, 7, or 8 a cycloalkyl group of carbon atoms, NR(15)R(16), phenyl or a nitrogen-containing heterocyclic ring having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein phenyl And nitrogen-containing heterocyclic ring is not substituted or 1 or -11- This paper scale applies Chinese National Standard (CNS) A4 specification (210 X297 mm) (please read the note on the back and fill out this page)

593307 Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives, Printing A7 B7 V. Description of Invention (1〇) Two substituents selected from the following: F, Cl, Br, I, CF3, N02, CN, NH2, OH, A Base, ethyl, decyloxy, dimethylamino, acesulfonyl, methanesulfonyl and methanesulfonamide; R(15) and R(16) together are 4 or 5 methylene chains , one of the CH 2 groups may be replaced by -0, -S-, -NH-, -N-(methyl) or -N-(benzyl); r is zero, 1, 2, 3, 4, 5 , 6, 7, 8, 9, 10, „11 or 12 R(5) is -Y-CsH2s-R(18) or phenyl; which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of : F, C, Br, I, CF3, N02, CN, NH2, OH, methyl, ethyl, methoxy, dimethylamino, sulfonyl, methanesulfonyl and methanesulfonamide; Y is -0- or -S-; S is 1, 2, 3, 4, 5, 6, 7, or 8; R(18) is hydrogen, CF3, C2F5, C3F7, with 3, 4, 5, 6 a cycloalkyl group of 7 or 8 carbon atoms, -COOR(21), NR(15a)R(16a), having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms Substituted nitrogen-containing heterocyclic ring, phenyl or thienyl, Phenyl and thienyl are unsubstituted or 1 or 2 -12-paper scales applicable to Chinese National Standard (CNS) A4 specification (210X 297 mm) (please read the notes on the back and fill out this page), - Ιτ 593307 A7 B7

Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives, Printing I. V. INSTRUCTIONS (11) Substituted from the following substituents, F, Cl, Br, I, CF3, sulfhydryl, methoxy, sulfonamide, methylsulfonate Mercapto and methanesulfonamide; R(15a) and R(16a) together are chains containing 4 or 5 methylene groups, one of which can be -0-, -S-, ··· , (methyl) or -Ν-(benzyl) substitution; R (21) is an alkyl group having 1, 2 or 3 carbon atoms; R(6) is OR(lOd) or OCOR(lOd); R( L〇d) is argon or an alkyl group having 1, 2 or 3 carbon atoms; B is hydrogen; or R(6) is a bond with B; and a physiologically tolerable salt thereof. Particularly preferred compounds of formula I are those wherein R(5) is attached at the position of the label 6, that is, the compound of formula la;

R(4> \^° R(3) N

R(6) R(2) R(1) 13- la This paper size is applicable to China National Standard (CNS) M specification (210x297 mm) (please read the notes on the back and fill out this page)

Lf. 593307 Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives, Printing A7 B7 V. Inventions (12) where R(l), R(2), R(3), R(4), R(5), R(6) And b are as defined above for preferred compounds. A very particularly preferred compound is a compound of formula la wherein R(1) and R(2) are independently hydrogen, CF3 or an alkyl group having 1, 2 or 3 carbon atoms; or R(1) and R(2) together have 2 3, 4, 5 or 6 carbon atoms of the extension bond; " R(3) is R(10)_CnH2n; R(l〇) is fluorenyl or CF3; η is 0, 1 or 2; R( 4) is R(13)-CrH2r wherein one CH2 group in the CrH2r group can be -〇, -CO-, -C0-0-, -0-C0-, -S_, -SO, -S〇r or NR (14) is substituted; R (14) is hydrogen or a burnt group having 1, 2 or 3 carbon atoms; R (13) is CH3, CF3, NR (15) R (16), phenyl or has 1, a nitrogen-containing heterocyclic ring of 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein the phenyl group and the nitrogen-containing heterocyclic ring are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, N02, CN, NH2, OH, sulfhydryl, -14- This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) (please read the precautions on the back) Fill in this page) Order 593307 A7 B7 \3/ V. Description of the invention ((Please read the notes on the back and fill out this page) Ethyl, methoxy, dimethylamino, sulfonamide Methanesulfonyl and methanesulfonylamino; R(15) and R(16) together are a chain of 4 or 5 fluorenylene groups, one of which can be -0-, -NH-, Ν · (Methyl) or -Ν-(benzyl) substitution; r is 0, 1, 2, 3, 4, 5, 6, 7, or 8; R(5) is -Y-CsH2s-R(18) Y S is 1, 2, 3, 4, group 5 or 6; R (18) is hydrogen, CF3, -COOR (21), NR (15a) R (16a), having 1, 2, 3, 4, An unsubstituted nitrogen-containing heterocyclic ring, phenyl or thienyl group having 5, 6, 7, 8 or 9 carbon atoms, wherein the phenyl group and the thienyl group are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of: F, C, Br, I, CF3, methyl, methoxy, sulfonamide, methanesulfonyl and methanesulfonamide; R (15a) and R (printed by employees of the Central Bureau of Standards and Staff of the Ministry of Economic Affairs) 16a) is a chain containing 4 or 5 methylene groups, one of which can be replaced by -Ο-, -S-, -NH-, -N-(indenyl) or -N-(benzyl) R(21) is an alkyl group having 1, 2 or 3 carbon atoms; R(6) is OH; -15- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) Central Economic Department Standard Bureau employee consumption cooperative printing 5 93307 A7 B7 V. INSTRUCTIONS (14) B is hydrogen; or R(6) is a bond with B; and its physiologically tolerable salt. Particularly preferred are compounds of the formula la, wherein R(l) and R(2) are fluorenyl; R(3) is methyl or ethyl; R(4) is R(13)-CrH2r, wherein the QHh group One of the 0112 groups may be replaced by -Ο-, -CO---C0-0_ or -0-C0; R(13) is CH3 or CF3; r is 0, 1, 2, 3, 4, 5, 6, 7 or 8; R(5) is -Y_CsH2s-R(18); Y is -Ο-; s is 1, 2, 3, 4, 5 or 6; R(18) is hydrogen, CF3, -COOR (21) A phenyl or thienyl group, wherein the phenyl group and the thienyl group are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, CF3, methyl or decyloxy; R ( 21) is an alkyl group having 1, 2 or 3 carbon atoms;

R(6) and B _-^6-_ This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) (please read the notes on the back and fill out this page)

593307 A7 B7 V. INSTRUCTIONS (15) Together as a bond; and its physiologically tolerable salt. Particularly preferred is also a compound of formula la wherein R(l) and R(2) are methyl; R(3) is methyl or ethyl; R(4) is R(13)-CrH2r, wherein (^ A CH2* group in the ί2ί group may be replaced by -Ο-, -CO-, -C0-0- or -0-C0; R(13) is CH3 or CF3; r is 0, 1, 2, 3, 4 , 5, 6, 7, or 8; R(5) is -Y-CsH2s-R(18); Y is -Ο-; s is 1, 2, 3, 4, 5 or 6; R(18) is hydrogen , CF3, phenyl or thienyl, printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back and fill out this page). The phenyl and thiophene groups are unsubstituted or 1 or 2 are selected from the following The substituent is substituted: F, Q, Br, CF3, decyl or methoxy; R(6) is OH; B is hydrogen; and its physiologically acceptable salt. The base and the extension base can be straight Bond or branch. This also applies to the formula CrH2r, CnH2n & CsH2s2 alkyl. The alkyl and alkyl groups are replaced _-17- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X297 mm) 593307

Or a part of another group, for example, when it contains a decyloxy group or a pyridyl group or a thiol group, it may be a straight chain or a branch. Examples of the hospital base are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl , 3,3-dimethylbutyl, heptyl, octyl, decyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, fifteen carbon Alkyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, decylalkyl. Examples of the divalent alkylene group derived from such groups are, for example, anthracene, 1,1, ethyl, i, anthracene, and I. Prolong propyl, L2 · propyl, 2, 2 · propyl, ι, 3- propyl,! , butyl, pentyl, 2,2-mercapto-1,3-dimethyl, 1,6-extension, and the like. (Please read the notes on the back and then fill out this page), τ Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives, Printed Paper Standards (CNS) A4g (21()><297 public) The nitrogen-containing heterocyclic ring of 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms is specifically an aromatic 1-, 2- or 3-pyrrolyl, bromo, 2-, 4- or 5-imidazole Base, 1·, 3_, 4- or 5-pyrazolyl, anthracene, 2,3-triazole-1·,-' or _5_yl, 1,2,4-triazole-ΐ_, _3_ or Base, or 5-tetrazolyl, 2-, 4- or 5-tetrazolyl, 3-, 4- or 5-iso-n-oxazole, 1,2,3, 嗤 4- 4- or 5- _, 1,2,4-oxadiazole _3_ or -5-yl, oxadiazole_2_ or _ 5-yl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 1,3,4-thiadiazole-2- or-5-yl, hydrazine, 2,4 thiadiazole _3- or 5-yl, 1,2,3-thiadi Oxazole-4- or-5-yl, 2-, 3- or 4-pyridyl, 2...4_, 5- or 6-pyrimidinyl, 3- or 4-indolyl, pyridinyl, 丨_, 2_ , 3_, 4_, 5_, 6_ or 7-fluorenyl, 1-, 2-, 4- or 5-benzimidazolyl, 3, 4, 5-, 6- or 7-oxazolyl, 2 -, 3-, 4-, 5-, 6-, 7- or 8-喳咁-18- 593307 The Ministry of Finance and the Central Bureau of Standards and Staff's Consumer Cooperatives printed A7 B7 7. Invented and suppressed the moon (17) — base, 1-, 3-, 4-, 5-, 6-, 7- or 8-isodecyl, 2_ , 4_, 5-, 6-, 7- or 8-carbazole, 3-, 4-, 5-, 6-, 7-10. ^ U base, 2_, 3_, 5-, 6...7- or 8-mercapto, 1_, 4_, 5... 6-, 7- or 8-fail 11 well base. Particularly preferred nitrogen-containing heterocycles are pyrrolyl, imidazolyl, anthracenyl, pyridinyl, pyridyl, pyridinyl, pyrimidinyl and hydrazine. The thienyl group is a 2- and 3-thienyl group. A monosubstituted phenyl group may be substituted at the 2_, 3_ or 4_ position, and the disubstituted phenyl group may be at 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or Replaced at 3,5_ position. This also applies in a similar manner to nitrogen-containing heterocyclic or thienyl groups. If the group is disubstituted, the substituents may be the same or different. If the R(1) and R(2) groups together are an alkylene chain, the groups form a ring together with the carbon atom to which they are attached, and the ring is bonded to the 6-membered ring of the formula by a carbon atom, that is, A spiro compound appears. If R(6) and B are together as one bond, a 2H chromene structure appears. If r(i... and R(11) together are a bond, then R(10)-CnH2n_NR (11> is the most nitrogen-heterocyclic ring bonded by a nitrogen atom. If the ruler (10) and R (11) ) is: a bond, and RdOVCnHyNIKll) - is a nitrogen azaindole bonded by a nitrogen atom, which is a ring of 4 members or a ring of more than 4 members, for example: 5 member ring, 6 member ring or 7 Preferably, when the compound of the formula I contains one or more acidic or basic groups or one or more basic heterocyclic rings, the invention also relates to corresponding physiologically or toxicologically tolerable salts, in particular Refers to the medicinal salt. Therefore, take -_:_-19- This paper size is applicable (CNS) A4· (2U)x297 DON)) --- (Please read the back note and fill out this page)

- order

Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives, Printed 593307 A7 B7 V. INSTRUCTIONS (Compounds of formula I with acidic groups (eg one or more COOH groups) may be, for example, metal salts (in comparison with sodium or potassium salts) Good) or a soil metal salt (for example: calcium or magnesium salt) or an ammonium salt (for example, a salt formed with ammonia or an organic amine or an amino acid) with one or more basic (ie, protons) A compound of formula I or a compound of formula I containing one or more basic heterocycles can be used with an inorganic or organic acid to form a physiologically acceptable acid addition salt, for example, hydrochloride, phosphate, sulfate, Methanesulfonate, acetate, lactate, maleate, fumarate, malate, gluconate, etc. If the compound of formula I forms an acid in the same molecule in addition to the above salt Or a basic group, the invention also includes an internal salt, the so-called betaine. The salt of the compound of the formula I can be obtained by a general method, for example, in a solvent or a dispersing agent, in combination with an acid or a base, or with other Salts undergo anion exchange. If the compound of formula I is suitable When substituted, stereoisomeric forms may occur. If the compound of formula I contains one or more asymmetric centers, it may have an S configuration or an R configuration, respectively. The invention includes all possible stereoisomeric forms, for example: An enantiomer or diastereomer, and two or more stereoisomeric forms, for example, a mixture of &isomers and/or diastereomers in any desired ratio. The present invention relates to enantiomers, for example, enantiomerically pure, including levorotatory and dextrorotatory enantiomers, or mixtures of two enantiomers in different ratios or racemic. In the case of cis/trans isomerism, the present invention relates to both cis and trans versions and mixtures thereof. Individual stereoisomers -20- This paper scale applies to the Chinese National Standard (CNS). A4 size (210X 297 mm) (Please read the note on the back and fill out this page)

593307 A7 B7 V. INSTRUCTIONS (19) When the method is right, the mixture can be resolved according to the general method, or for example, stereoselective synthesis. The invention also includes all tautomeric forms of the compounds of formula I if they contain a mobile hydrogen atom. The compounds of formula I can be prepared by a variety of different chemical methods which are also part of the subject matter of the present invention. Thus, the compound of formula I is prepared by a) a compound of formula II, s/R (3)

0 C R (4),

N , Μ R(4) Ο

Ministry of Economic Affairs t 矣Standards Bureau employee consumption cooperatives%% R(l), R(2) and R(5) as defined above, react with sulfonamide of formula III, where Han (3) and R (4) The above definition, and hydrazine is hydrogen or a metal equivalent, preferably lithium, sodium or potassium, or μ is also preferably a trialkylsulfanyl group, for example: a tridecyl group, forming a chromatid of the formula Ib, or b) The lb compound is in a manner known per se, with the formula κ (1〇(1)4 burning agent or the formula R(10d)-COL·deuterating agent or the formula (R(1〇d)_c〇) 2 phthalic anhydride, wherein R (l〇d) as defined above and L is a nucleophilic cleavage group, specifically F, Cl, Br, I, sulfonyloxy or p-benzenesulfonyloxy, in alkylation or deuteration Reacting to produce a compound of formula Ic, wherein R(6) is OR(lOd) or OCOR(lOd); -21· (please read the notes on the back and fill out this page)

This paper scale applies to the Chinese National Standard (CNS) A4 specification (2l〇x297 mm) 593307 R(4) 〇 • S· *R(3)

Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of Invention (20 R(4) 〇

IT *R(3)

Lc or c) from the compound of formula lb R(4) 〇

IT, S·R(3)

Wherein 11(1), 11(2), 11(3), 11(4) and &(5) are converted to a compound of formula I, wherein R(l), R(2) R are as defined above in the elimination reaction. (3), R(4) and R(5) are as defined above; or d) are compounds of formula IV R(4)

IT - Η

R(6) R(2) R(1) -22- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page)

593307

V Department of Economics, Central Bureau of Standards, Staff Consumer Cooperatives, Printing A7 B7 V. Inventions (21) where R(l), R(2), R(3), R(4), R(5) and R(6) Reacting with the sulfonic acid derivative of the formula V as defined in claims 1 to 6 of the patent range 〇\〇\\ // W R(3) wherein R(3) is as defined above, and W is a nucleomeric leaving group, such as, for example, : bromine, 1-imidazolyl, but especially gas; or e) from the compound of formula VI N"

R(6) R(2) R(1) wherein R(l), R(2), R(3), R(5) and R(6) are as defined in the scope of claims ii to ,, and M is Hydrogen or a metal equivalent, preferably lithium, sodium or potassium, reacted with a blowing agent of formula VII in a firing reaction in a manner known per se

R(4)-L VII where R(4) and L are as defined above; or -23· This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) (please read the notes on the back and fill in the form) This page)

593307 A7 B7 V. INSTRUCTIONS (22) f) From the compound of formula VIII R(4)V?0 S II R(3)

R(6) R(2) R(1)

VIII Ministry of Economic Affairs Central Bureau of Standards and Staff Employees' Cooperatives prints the definitions of R(l), R(2), R(3), R(4), R(6) and B as in the scope of applications for patents 1 to 6. The R(18)-CsH2s-L compound is reacted in an alkylation reaction wherein R(18), s and L are as defined above. Process a) corresponds to the nucleophilic reaction using a sulfonamide of the formula III or a salt thereof to open the epoxide of the formula II. If free sulfonamide (Formula III, M=N) is used, it is preferred to first react with a base to form a sulfonamide salt (Formula III, M = metal cation), and the reaction of the sulfonamide to remove the proton-forming salt can be used in the original Bit is carried out. It is therefore preferred to use a base which does not participate as a nucleophile in the reaction, such as, for example, sodium hydride, sodium carbonate, potassium carbonate, sterically strongly masked amines such as dicyclohexylamine, N,N-bicyclic Hexylethylamine, or other strong nitrogen bases of low nucleophilicity, for example: DBU (diazobicycloundecene), N, N', N'''-triisopropyl hydrazine, and the like. However, bases commonly used in this reaction can also be used, such as potassium t-butoxide, sodium decoxide, alkali metal hydrogencarbonates, alkali metal hydroxides such as, for example, LiOH, NaOH or KOH, or soil-measured metal hydroxides. For example, Ca(〇H)2. -24- (Please read the notes on the back and fill out this page) Order · This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) Printed by the Central Bureau of Standards and Staff of the Ministry of Economic Affairs 593307 A7 B7 , invention description (23) The amount used is stoichiometric or coal impact. It has been found to be particularly advantageous when free sulfonamide is used in the presence of less than a stoichiometric amount (e.g., 20 to 70%) of a suitable base (e.g., sodium hydride). The reaction is preferably carried out in a solvent, and is particularly preferred in polar organic tanning agents such as, for example, dimercaptodecylamine (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), Tetramethylurea (TMU), tridecylphosphonium hexaphosphate (HMPT), tetrahydrofuran (THF), dimethoxyethane (DME), etc., or may also be, for example, in a hydrocarbon (eg, toluene) Or in a halogenated hydrocarbon (eg chloroform or dioxane, etc.). However, the reaction can also be carried out in a polar protic solvent such as, for example, water, methanol, ethanol, isopropanol, ethylene glycol or oligomers thereof and their corresponding half ethers or scales thereof. The reaction can also be carried out in a mixture of such solvents. However, it is also particularly preferable to carry out the reaction without using a solvent. The reaction is preferably carried out at a temperature ranging from -10 to +140 ° C, particularly preferably in the range of from 20 to 100 ° C. Another preferred method for carrying out this reaction defines the use of a sulfonamide derivative of the formula III wherein hydrazine is a trialkyl fluorenyl group, for example a tridecyl group. This is preferably carried out in the presence of fluoride, for example tetrabutylammonium fluoride. The epoxide of formula II is prepared from the corresponding olefin of formula IX according to methods known in the literature.

R(1) -25- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page)

593307 A7 B7 V. INSTRUCTIONS (24) where R(l), R(2) and R(5) are as defined in paragraphs 1 to 6 of the scope of application, for example, by the use of suitable inorganic or organic peroxides. For example, H2〇2 or m-chloroperbenzoic acid, or by catalyzing the cyclization of the corresponding bromo alcohol with a base, the bromool is prepared by reacting IX with, for example, N-bromosuccinimide and water. The olefin of formula IX can be reduced to a hydrazine H functional group from a group of a ketone of formula X, followed by acid catalyzed elimination or thermal cyclization from an appropriately substituted arylpropargyl ether as described, for example, in j.Org. Chem. 38 (1973) 3832 〇 (Please read the notes on the back and fill out this page)

x Ordering of the Ministry of Economic Affairs, Central Bureau of Employees, Consumer Cooperation, Printing Method b) illustrates that a compound of formula lb according to the invention is converted to a further compound of formula Ic according to the invention via a 3-hydroxyalkylation or oximation reaction. When alkylation is carried out, the alcohol is reacted with a suitable base (for example, sodium hydride) to be converted into an alkoxide, which is further combined with an alkylating agent of the formula R(l〇d)-L in a suitable polar solvent. For example, dimethylformamide is reacted at a temperature of 20 to 150 °C. The reaction of the alcohol to remove the proton-producing salt can also be carried out in situ. At this time, it is preferred to use a base which does not burn, such as, for example, potassium carbonate. Other suitable bases and solvents include those described in Process a). The oximation reaction of the compound of formula lb is preferably carried out using the corresponding anhydride of formula (R(l〇d)-C0)20 in a suitable polar solvent (eg pyridine or dimethylformamide), and if appropriate -26- Paper scale applicable to China National Standard (CNS) A4 specification (210X297 mm) 593307 Ministry of Economic Affairs Central Bureau of Standards Staff Consumer Cooperatives Print A7 B7 V. Invention Description (25) When adding 'chemical catalysts, such as: two Methylamino σ is carried out than biting. Method C) illustrates that the lb color full alcohol is converted to the ionic chromene by elimination reaction. The chromanol can be directly dehydrated in the presence of an acid or a base, or the hydroxyl group can be activated first, for example, by acetonitrile with acetic anhydride (see method b), or by mesylation with sulfonium sulfonate, followed by The base catalyzed elimination reaction, for example: heating with DBU (diazobicycloundecene). Method d) illustrates a conventional reaction known per se which is a reactive sulfonyl compound of the formula V, in particular a chlorosulfonyl compound (W=C1), which is reacted with an amine derivative of the formula IV to give the corresponding formula I Sulfonamide derivatives. In principle, the reaction is carried out without using a solvent, but in most cases, these reactions are carried out using a solvent. The reaction is preferably carried out using a polar solvent, preferably in the presence of a base, and the base is preferably used as a solvent, for example, when triethylamine is used, specifically, when pyridine and its homologue are used. Solvents which may also be used are, for example, water, aliphatic alcohols such as methanol, ethanol, isopropanol, second butanol, ethylene glycol and monomers thereof, and oligomeric monoalkyl and dialkyl ethers, tetrahydrofuran, Dioxane, dialkylated guanamine such as: DMF, DMA, and TMU and HMPT. The reaction is between 〇 and 160. (At the temperature, preferably at 20 to 1 Torr. The oxime is carried out. The amines of the formula IV are known in the literature, preferably by the formula η epoxide similar to the a) method, using the formula R (4) The appropriate amine of -NH2 is subjected to a nucleophilic ring opening reaction. -27- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) (please read the notes on the back and fill out this page). The Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives, Printed 593307 A7 B7_ V. Description of the invention (26) Process e) represents a known alkylation reaction which is carried out by reacting a sulfonamide or a salt thereof with an alkylating agent of the formula VII. Thus, the sulfonamide is first converted to form a salt thereof, and the purpose is to use a suitable base and solvent in the process a), and the salt and the alkylating agent of the formula VII, at 15 to 150. (Reaction at a temperature of: VI. Sulfonamide according to the literature, preferably from the epoxide of formula II, using the formula R(3)-S02NH2 as appropriate to continue the amine, similar to the method described in item a) A nucleophilic ring opening reaction, however, a stoichiometric test should be used at this time. Process f) illustrates the alkylation of a phenol of formula VIII with an alkylating agent of formula R(18)-CsH2s-L. Therefore, the benzene is first reacted with a suitable test (for example, sodium hydride or seletonide) to be converted into a phenate, and then in a suitable polar solvent such as, for example, dimethylformamide or dimethylamine. The guanamine is reacted with an alkylating agent at a temperature of from 2 Torr to 150 °C. The reaction of the alcohol to remove the proton-forming salt can also be carried out in situ, in which case it is preferred to use a base which does not burn, such as, for example, potassium carbonate. Other suitable bases and solvents which may be employed include those described in Process a). Formula VIII is prepared by the method described in &) to e), but each R(5) is OH or OR (R is a suitable protecting group, for example, benzyl), and the protection is continued later. base. In all methods, in some reaction steps, it is suitable for temporary protection ------—________ _28_ This paper is also suitable for A4 secret (21GX 297 public ^----- (please read the back) Please fill out this page again)

593307 A7 27> V. INSTRUCTIONS INSTRUCTIONS (Professionals of the relevant technical experts of the Protection Group Technical Section. The protective groups selected by the Special Group have been described in the literature, if appropriate, 彳I, /, The method K Τ is suitable for each case. Two =: The compound has a surprisingly strong 且+ channel and the specific two =? The effect of this κ+ channel is adenosine monophosphate ^ and basically the same as the conventional c The (ATP) channel is different, and the Iks channel is very similar in the heart muscle of the channel type κ>ΑΜΡ) channel, and even the same, according to the Ike of the scorpion Second, the Iks channel, which is expressed in the claw-cell, exhibits a strong blocking effect. Therefore, this fine action on the Iks channel allows the compound according to the present invention to exhibit a high degree of w (four) way of action in the living (4), and is highly suitable as a pharmaceutically active compound for treating and preventing various symptoms. The compounds of the formula I according to the invention are therefore novel active compounds which are potent inhibitors of irritating gastric acid secretion. The compounds of formula I are therefore useful as pharmaceutically active compounds for the treatment and prevention of stomach and intestinal ulcers (e.g., duodenal ulcers). Because of its potent inhibitory effect on gastric acid secretion, it is also highly suitable as a medical agent for the treatment and prevention of reflux esophagitis. Another feature of the compounds of the formula I according to the invention is that it is suitable as a pharmaceutically active compound for the treatment and prevention of diarrhea. The compound of the formula I according to the invention is still suitable for the treatment and prevention of cardiovascular ___ -29- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) f Please read the notes on the back and fill out this page) Order - Ministry of Economic Affairs Central Bureau of Standards Staff Consumer Cooperatives Printed Economy Ministry Central Bureau of Standards Staff Consumer Cooperatives Printed 593307 A7 B7_____ --- V. Inventions (28) Medically active compounds for diseases. It is especially useful for the treatment and _ all the arrhythmia, including: atrial, ventricular and upper ventricular dysplasia, especially < arrhythmia that is eliminated by prolonging the action potential. It is especially useful for the treatment and prevention of atrial fibrillation and atrial flutter, and for the prevention of re-entry into arrhythmia and prevention of sudden cardiac death due to ventricular fibrillation. Although there are many kinds of substances on the market that have anti-arrhythmia activity, but there are no compounds with satisfactory activity, range of sputum and action mode, there is still a need to develop improved antiarrhythmic agents - many kinds of so-called III The known anti-arrhythmia agent is based on prolonging the action potential time to increase myocardial reflex time. This is essentially determined by the repolarization κ+ flow of the efflux cells via various K+ channels. The special focus of this paper is the so-called "delayed rectifier" Ik, which has two subtypes, a rapidly activated Ikr' and a slowly activated Iks. Most known Class III antiarrhythmic agents are mainly Or only block Ikr (eg, dofetilide, d-sotalol). However, these compounds are known to increase the risk of anterior arrhythmia when the heart rate is low or normal. This kind of arrhythmia is particularly characterized by "Torsades de pointes" (DM, Roden, "Current Status of class III Antiarrhythmic Drug Therapy", Am· J. Cardiol, 72 (1993), 44B-49B). If the heart rate is high or the receptor is not stimulated, the effect of the Ikr blocker to prolong the action potential is __ _30_ This paper scale applies to the Chinese national standard (CNS) A4 size (2丨〇'〆297mm) """ ~— (Please read the notes on the back and fill out this page)

1T 593307 A7 B7 V. INSTRUCTIONS (29) The printing of the Consumers' Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs has dropped significantly. This is because under these conditions, Iks has a stronger influence on repolarization. For these reasons, the substance according to the present invention having the action of Iks blocker has significant advantages over the known Irk blocker, and the inhibition and inhibition of Iks channel are also described herein by, for example, 10,000-adrenergic stimuli. Sexual over-stimulation induces a correlation between life-threatening arrhythmia (eg, TJ Kolasky), (: Η·Follmer and CF·starmer) “Anti-heart rhythm Channel Specificity in Antiarrhythmic Drug Action; Mechanism of potassium channel block and its role in suppressing and aggravating cardiac arrhythmias; Circulation 82 (1990), 2235-2242; Busch, K. Malloy, WJ Groh, MD Warnum, JP Edman ( Adelman) and J. Maylie "The novel class III anti-arrhythmia NE-10064 and NE-10133 inhibit the Iks channel of Xenopus and the Iks channel of guinea pig cardiomyocytes" (The novel class III antiarrhythmic) s NE-10064 and NE-10133 inhibit Iks channels in Xenopus oocytes and Iks in guinea pig cardiac myocytes ), Biochem, Biophys, Res, Commun, 202 (1994), 265-270). In addition, such compounds can significantly improve cardiac dysfunction, particularly congestive heart failure, which is preferably used in combination with active compounds that promote contraction (positive effects on contraction), such as phosphodiesterase inhibitors. -31- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) (please read the notes on the back and fill out this page)

Order

Ministry of Economic Affairs Central Bureau of Standards Staff Consumer Cooperatives Printed 593307 Α7 ______ Β7 V. Invention Description (30) Although the blocking of Iks can achieve medical advantages, so far only a very small number of compounds can suppress this "delay correction," It is currently recognized that the developing substance aziniilide also has a blocking effect on Iks' but mainly blocks Ikr (selectivity is 1:10). w〇-A_95/14470 applies for benzodiazepine箪 is used as a patent for the use of Iks selective blockers. Other Iks blockers are described in FEBS Letters 396 (1996), 271-275: “Special blocking of chromatin on slow-activated Iks channels” ( Specific blockade of Slowly activating Iks channels by chromanols ····”, and pfKigers Arch.-Eur. J· ^Physiol 429 (1995), 517-530·”: a novel inhibitor of CAMP regulation of Cl secretion in rabbit colon, "A new class of inhibitors of cAMP mediated Cl-secretion in rabbit colon , acting by the reduction of cAMP-activated K+ conductance"". However, the 3-primary color is explained. The efficacy of the alcohol is still lower than the compound of the formula I according to the invention. The compounds of the formula I according to the invention and their physiologically tolerable salts can be used in animals, preferably in mammals, in particular humans, which are themselves useful as medicaments Mixing with each other or forming a pharmaceutical dosage form. The invention also relates to the use of a compound of the formula I and a physiologically tolerable salt thereof for use as a medicament for the treatment and prevention of the above-mentioned conditions, and for the manufacture of such medicaments and with K+ channels In addition, the present invention relates to a pharmaceutical preparation comprising at least one compound of the formula I as an active ingredient and/or a physiologically tolerable salt thereof and a conventional medical use- 32- This paper scale applies to China National Standard (CNS) Α4 specification (210X297 DON) (please read the notes on the back and fill out this page)

593307 A7 B7 V. INSTRUCTIONS (31) Toxic excipients and adjuvants. The pharmaceutical preparations usually comprise from 0.1 to 90% by weight of the compound of the formula I and/or its physiologically tolerable salts. The pharmaceutical preparation can be prepared in a manner known per se. Thus, a compound of the formula I and/or a physiologically tolerable salt thereof, together with one or more solid or liquid pharmaceutical excipients and/or adjuvants, and if desired, in combination with other pharmaceutically active compounds, form a suitable The dosage form or dosage form can be used in human medicine or veterinary medicine. The medicament containing the compound of the formula I according to the invention and/or its physiologically tolerable salt can be administered orally, parenterally, for example, intravenously, rectally, inhaled or topically, preferably by individual administration. The situation varies, for example: the specific process of the disease to be treated. Relevant skilled artisans are familiar with the type of ancillary material suitable for the desired pharmaceutical formulation. In addition to solvents, gel formers, suppository bases, lozenge aids, and other active compound carriers, for example, antioxidants, leveling agents, emulsifiers, defoamers, taste modifiers, preservatives, dissolution agents can be used. An agent, a buffer substance or a colorant that achieves a storage effect. The compounds of formula I can also be combined with other pharmaceutically active compounds to achieve a beneficial medical effect. Therefore, in the treatment of cardiovascular disease, it is preferable to combine with a substance having a cardiac jk tube activity. Such a combination of components suitable for cardiovascular disease is, for example, other antiarrhythmic agents, ie, class I, II or III antiarrhythmic agents, such as, for example, an Ikr channel blocker, such as: Toffee ( Dofetilide), or other antihypertensive substances such as ACE-33- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 3⁄4 (please read the notes on the back and fill out this page)

P Ministry of Economic Affairs Central Bureau of Standards Staff Consumer Cooperatives Printed 593307 A7 Β7 V. Invention Description (32 Ministry of Economic Affairs Central Bureau of Standards Staff Employees Cooperatives Printed Preparations (eg: enalapril, captopril, 阮米普 ( Ramipril)), angiotensin antagonists, K+ channel activators, and α- and β-receptor blockers, and sympathomimetic compounds and compounds with adrenergic activity, and Na+/H+ exchange inhibition Agents, calcium channel antagonists, phosphodiesterase inhibitors and other substances having positive effects on contractile activity, such as, for example, digitoxin, or diuretics, in combination with antibiotic active substances and antiulcer agents It is also advantageous to 'for example: in combination with sputum: antagonists (for example: ranitidine, cimetidine, fametidine, etc.), especially for the treatment of gastrointestinal disorders. For the preparation of the oral form, the active compound is mixed with an additive suitable for the purpose, such as an excipient, a stabilizer or an inert diluent, and converted into a suitable drug by a conventional method. For example, lozenges, coated lozenges, hard gelatin capsules or aqueous, alcoholic or oily solutions. Inert excipients which can be used are, for example, gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate lactose, glucose or starch. , in particular, corn starch. This preparation can be made into dry or wet granules. Examples of suitable oily excipients or solvents are vegetable oils or animal oils, such as sunflower oil or salmon oil. Suitable solvents for aqueous or alcoholic solutions are For example, water, ethanol or sugar solutions or mixtures thereof may also be used in other dosage forms of adjuvants such as polyethylene glycol and polypropylene glycol. For subcutaneous or intravenous administration, the active compound, if desired, Commonly used substances, such as: solvent, emulsifier, or other auxiliary --- -34- This paper scale is suitable for China Ping

δ 0 A y IN PCT 7 9 2 (Please read the notes on the back and fill out this page) Order 593307 A7 B7 V. INSTRUCTIONS (33) The co-agents form a solution, suspension or emulsion. The compound of formula I and its physiologically tolerable salts can also be lyophilized, and the resulting lyophilizate can be used, for example, in the manufacture of a preparation for injection or infusion. Examples of suitable solvents are: water, physiological saline solution, or alcohols such as ethanol, propanol or glycerol, and sugar solutions such as glucose or mannitol solutions, or mixtures of such different solvents. Examples of pharmaceutical formulations suitable for administration in the form of an aerosol or spray are those which are contained in a pharmaceutically acceptable solvent such as, in particular, ethanol or water, or a mixture of such solvents, or a physiologically acceptable compound thereof A solution, suspension or emulsion of a tolerated salt. The formulation may also contain other pharmaceutical auxiliary substances such as surfactants, emulsifiers and stabilizers, and propellants if desired. Typical active compound levels in such formulations are from about 0.1 to about 10, specifically from about 0.3 to about 3% by weight. Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back and fill out this page). The dosage of the active compound of formula I or its physiologically tolerable salt is determined on a case-by-case basis and usually needs to be achieved. The best results in individual cases. Therefore, of course, depending on the frequency of administration of the compound used for treatment or prevention, and the duration of action and duration of action, depending on the nature and severity of the disease to be treated and the age, sex, weight and individual response of the human or animal to be treated and This treatment is based on acute treatment or prophylaxis. Typically, a daily dose of a compound of formula I administered to a patient weighing 75 kg is from 0.001 mg/kg body weight to 100 mg/kg body weight, preferably from 1 mg/kg body weight to 20 mg/kg body weight. The dose can be in a single dose or divided into several small doses. (Example: two, three or four small doses -35- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 593307 A7 B7 V. Invention description (34) Quantity type investment . Especially when treating acute arrhythmia, such as in an intensive care unit, parenteral administration is also recommended by injection or infusion (e.g., intravenous continuous infusion). The above compounds of formula I can also be used as intermediates in the preparation of other pharmaceutically active compounds. Experimental partial abbreviations list DBU 1.8-diazobicyclo[5.4.0]undec-7-ene DMF Ν, Ν-dimethylformamide DMSO dimethyl sulfoxide 乙酸乙酯 ethyl acetate mp melting point (unless otherwise stated Otherwise, the melting point of the unpurified crude product is shown; the melting point of each pure substance may be higher) i.vac. vacuum sol. Solvent NBS N-bromo amber quinone imine RT Room temperature Ministry of Economic Affairs Central Bureau of Bureau staff consumption cooperative printing (please Read the precautions on the back and fill out this page.) THF Tetrahydrofuran Example 1: (earth) trans-N-(6-methoxy-3-carbyl-2,2-dimethylchroman-4-yl)- N-methylmethanesulfonamide-36- This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 593307 A7 B7 V. Invention description (35)

a) 2,2-dimercapto-6- via base color full-4-copper 1 liter of acetonitrile containing 100 g (0.65 mol) of 2,5-dihydroxyacetamidine, 130 ml (1.55 mol) pyrrole The reaction mixture of pyridine and 290 ml (3.95 mol) of acetone was at 45. (The next heating is 8 hours. The solvent is removed in vacuo, the residue is dissolved in 1 liter of EA. The organic phase is diluted twice with dilute hydrochloric acid, stirred with activated carbon, dehydrated with magnesium sulfate, and concentrated. The residue is stirred with petroleum ether. The precipitate was filtered off to give 102 g of 2,2-dimethyl-6-hydroxychroman-4-one, mp 161 ° C. b) 6-octyloxy-2,2-dimethylchroman Printed by the Central Bureau of Standards Staff Consumer Cooperative (please read the notes on the back and fill out this page). Add 25.2g (131.2 millimoles) of 6-hydroxy-2,2-dimethylchromate at RT. After adding 18.0 g (131 mmol) of potassium carbonate powder to -4-ketone to 350 ml of diethyl ketone, the mixture was stirred at 75 ° C for 30 minutes. After cooling to 60 ° C, 15.7 ml (131 mmol) of benzyl bromide was added dropwise. After 2 hours, the mixture was concentrated in vacuo, and the residue was applied with water and filtered, filtered, solid, 37 g, mpl. -Benzyloxy-2,2-diindenylchroman-4-ol containing 20.0 g (71 mmol) of 6-benzyloxy-2,2-dimethylchroman __-37-_ ^ paper The scale applies to China National Standard (CNS) A4 specification (210X297 mm) 593307 A7 V. Description of invention (36) with 2.94 g (78 mmol) of sodium borohydride in 1 ml of methanol and 300 mM red alcohol solution RT was placed for 3 hours. The reaction mixture was poured into 1300 ml of ice water, and the precipitate was filtered under suction and dried under reduced pressure. Yield gram 6 noon oxy-2,2-dimethylchroman-4-one, ηι·ρ· 83-84. C. d) 6-+oxy-2,2-dimethyl-2H_chromene 3 9.6 g (33.8 mmol) 6-benzyloxy-2,2-dimethylchroman _' alcohol and hydrazine · 2 g of p-toluene in 85 ml of toluene solution on a water separator's under heating for 丨 hours, after cooling, the strips were washed twice with aqueous solution of Wei-hydrogen sodium, dehydrated by sulfur, concentrated in vacuum, 7.6 6-Benzyloxy-2,2-dimethyl-2-indole-chromene e) 6·benzyloxybromide 2,2-dimethylchroman-4-ol is added in one dose at a time. 5.05 g (28.3 mmol) The Ministry of Economic Affairs standard staff eliminates the co-production of 7.5 g (28.2 mmol) 6 节 氧基 % 二 · ( 色 9 9 9 9 9 9 9 In milliliters (48.7 milligrams) of water, the mixture is under the RT __ night. The reaction mixture was poured into a milliliter of water, and then mixed for 1 hour to aspirate the transitional sediment, washed with water, and dried. Produces 9.5 g of 6·octyloxy_3_ desert dimethyl color fullerol, πι·ρ·126-128·(:.f) 6-benzyloxy-2,2-dimethyl_3, 4- epoxy color full containing 9.5 grams (28.5 millimoles) 6 · hydroxy d prepared a: methyl color · 4 · alcohol 100 ml TMF solution, and 4.6 g (82 mmol) Potassium powder (4)-night. All filtered through sputum salt, sputum was concentrated using a rotary evaporator, yielding 8.3 g of 6·pre-oxyindole dimethyl _ ^ -38- This paper is again applicable ( CNS ) A4 specification (21GX297 Gong ^ --- -- 593307 A7 B7 V. Description of the invention (37 ) 3,4-epoxy full mp70-72X g) N-(6-decyloxy-3-carbyl-2,2- Diterpenoid 4-mercapto-4-yl)methyl-sulfonamide was added dropwise with 7.5 ml of DMSO containing 4.25 g (39 mmol) of methyl sulfonamide to 0.21 g (7 mmol) 80% In a 15 ml DMSO suspension of sodium hydride, the mixture was stirred at RT for 30 minutes, then 8.2 g (29 mmol) of benzyloxy-2,2-dimethyl-3,4-epoxy was added dropwise. The mixture was filled with 18 ml of DMSO solution, and all were heated at 5 CTC for 2 days. The mixture was poured into water, and the transition precipitate was suctioned and dried under reduced pressure to give 8.8 g of N-(6·decyloxy-3-carboyl-2 2· dimethylchroman-4-yl)decyl-nonylsulfonamide, mp 162-164X. Example 2: (±)-trans-N-(6-benzyloxy-3-ethenyl-2 , 2_dimercaptochroman-4-yl)-N-methyl-methanesulfonamide

Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back and fill out this page). Take 4.5 g of N-(6-benzyloxy-3-hydroxy-2,2-dimercapto-4 • A solution of hydrazino-nonylsulfonamide in 37 ml of pyridine in 37 ml of acetic anhydride was allowed to stand at RT overnight. The whole was concentrated under reduced pressure, and the residue was dissolved in EA, and washed with dilute hydrochloric acid and saturated sodium hydrogen carbonate solution, and dehydrated with sulfuric acid. -39- The paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) W307, invention description Bu-reducing solvent, resulting in 4.7 g N- (6_oxylated winter ethylene 2,2_ Diterpene base color-4-yl)-N_indolyl methanesulfonamide m p. 124_125 · ^. Example 3: (±)-trans-N-(6-benzyloxy-3-methoxy-2,2-dimethylchroman-4-yl)-N-methyl-methyl decylamine

(Please read the notes on the back and fill out this page.) The Ministry of Economic Affairs' Central Bureau of Standards and Staff Consumer Cooperatives prints 0.5 g (1.3 mmol) of N_(6-benzyloxy-3-hydroxy_2,2_dioxin The base color 4-yl)-N-mercapto-nonylsulfonamide (Example lg) was dissolved in 4 mL of DMF and added dropwise to a solution of 0.05 g (1.7 km) of sodium hydride in 3 mL of DMF. in. The mixture was stirred at rt for 30 minutes, 〇·25 g (1.8 mmol) of decyl iodide was added, and the mixture was stirred at RT for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water and ea <'> organic phase washed with dilute hydrochloric acid and saturated aqueous solution. Dehydration by sulphuric acid and concentration under reduced pressure gave 0.52 g of N-(6-benzyloxy-m-methoxy-indolyl-4-yl)-N-indolyl-methionin, mp 119_ 12TC 〇 4: N-(6-benzyloxy-2,2-dimethyl-2H-chromene-based) fluorenyl-nonylsulfonamide-40- This paper scale applies to China National Standard (CNS) A4 specification (210X297 Amendment i. 593307 A7 B7 V. Description of invention (39)

Containing 1.0 g (2.3 μm) of N-(6-benzyloxy-3-ethenyloxy-2,2-diindolyl-4-yl)indolyl-methyl urethane (example) 2) and 2.2 g (13.8 mmol) of DBU in 4.2 ml of toluene were heated at 105 ° C for 5 hours. The reaction mixture was diluted with EA and washed with hydrochloric acid until the aqueous layer was acid. The mixture was washed with a sodium hydrogencarbonate solution, dried over magnesium sulfate and concentrated in vacuo to give <RTI ID=0.0>> Sulfonamide. Example 5 · (士)-反N-(6-butoxy-3-based-2,2-dimethylchroman-4-yl)-N-methyl-indole

Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back and fill out this page) a) 6 - Butyrate-based 2,2·dimethyl-formed 4-嗣 drop plus 50g ( A solution of 0.26 moles of 2,2-dimercapto 6-hydroxychroman-4-one (Example la) in 500 mL of DMF was added to a suspension of 9.0 g (0.3 mol) of 80% sodium hydride in 500 mL of DMF. Mixture on _-41- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 593307 A7 B7 V. Invention description (4〇), stir for 90 minutes at RT, add 49 g (0.265 m) Iodine, the mixture was stirred at RT for another 90 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was combined with water and evaporated. The organic phase was washed with a 5M aqueous sodium hydroxide solution, stirred with activated carbon and magnesium sulfate, filtered and concentrated. 57.6 g of 6-butoxy-2,2-dimercaptochroman-4-one were produced. b) 6-butoxy-2,2-dimethyl-2H-chromene Similar to the method of lc and Id, prepared from 6-butoxy-2,2-dimethylchroman-4-one . Alternatively, the compound can be obtained by the following route: 4.5 g (150 mmol) of 8Q, % sodium hydride is added dropwise at RT, and after 15 minutes, 23 g (224 mmol) of 3-chloro is added dropwise. -3-Methylbutyne was added to a solution of 25 g of 4-butoxyphenol (150 mmol) in 350 ml of toluene, and the mixture was heated under reflux for 10 hours. After cooling, the mixture was washed with aq. c) 6-butoxy-3-bromo-2,2-dimethylchroman-4-ol analogously to the method of Example, from 6-butoxy-2,2-dimethyl-2oxime-chromene Made, mp72-74 ° C. Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back and fill out this page) d) 6-Butoxy-2,2-dimethyl-3,4-epoxy color similar example If , 0.8 g of 6-butoxy-2,2-di, from 1·g (3 mmol) of 6-butoxy-3-bromo-2,2-dimethylchroman-4-ol Indole-3,4-epoxy color oil. e) N-(6-butoxy-3-hydroxy-2,2-dimethylchroman-4-yl)-N-methyl-valetene-glycoside-42- This paper scale applies to Chinese national standards (CNS) A4 size (210 parent 297 mm) 593307 A7 B7 V. Description of invention (41) Add 1 ml of DMSO containing 0.47 g (4.3 mmol) of N-mercaptomethylsulfonamide to 0.02 g ( In a 2 ml DMSO suspension of 0.7 mmol of 80% sodium hydride, the mixture was stirred at RT for 30 minutes. A solution of 0.8 g (3.2 mmol) of 6-butoxy-2,2-dimethyl-3,4-epoxy full 1 ml of DMSO was added dropwise, and all were allowed to stand at RT for 5 days, and then After heating at 50 ° C for 9 hours, the mixture was poured into water, and the precipitate was filtered under suction and dried thoroughly under reduced pressure to give <RTI ID=0.0>> Base color-4-yl)-1^-indenyl-A-branched amine, 111々. 138-140. 〇 „ Example 6: (±)-trans-N-(3-acetoxy-6-butoxy-2,2·dimethylchroman-4-yl)methyl-indole amine (please Read the notes on the back and fill out this page.)

The Employees' Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed a similar example 2, which consisted of 0.7 g of Ν-(6-butoxy-3-hydroxy-2,2-dimercaptochroman-4-yl)-fluorene-fluorenyl - A continuous loading of amine and 6.5 liters of acetic acid Sf in 13 ml of pyridine to obtain 0.6 g of N-(3-acetoxy-6-butoxy-2,2-diindenyl-4-yl) -N-mercapto-sulfonamide, mp 87-89 ° C. Example 7: N-(6-Butoxy-2,2-dimethylchromen-4-yl)indolyl-nonylsulfonamide-43- This paper scale applies to China National Standard (CNS) A4 specification (210X) 297 mm) 593307 Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives, Printing A7 B7 V. Invention Description Q)

Containing 0.5 g (1.3 mmol) of N-(6-butoxy-3-ethenyloxy-2,2-diindolyl-4-yl)-N-indenyl-phthalocyanine (Example 6) and 1.1 g (7.5 mmol) of DBU in 2.5 ml of toluene solution were heated at 105 ° for 60 hours. The reaction mixture was diluted with EA and washed with hydrochloric acid until the aqueous layer was acid. The mixture was washed with a sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo to yield <RTIgt;<RTIgt;<&RTI&&&&&&&&&&&&&&&&&&&Indoleamine; mp 114-116 · C Example 8: (±)-trans (6-propionyl-3-yl-based-2,2-dimethylchroman-4-yl)-N-indenyl Sulfonamide

a) N-( 3.6-di-diyl-2,2-dimercaptochroman-4-yl)-N-fluorenyl phthalocyanine-44- This paper scale applies to China National Standard (CNS) A4 specification ( 210X 297 mm) (Please read the notes on the back and fill out this page)

593307 A7 B7 1. Description of the invention (43 Take 1·〇克(2·6 mmol) (±) _反-N_(6_benzyloxy-3-hydroxy-indenyl-4-yl) fluorenyl - Vermiculite 1 (Example 1) was hydrogenated in 100 ml of THF / methanol (1:1) in the presence of palladium on carbon until the absorption of helium ceased. The catalyst was filtered off and the filtrate was concentrated to give hydrazine. · 7 g Ν · (3,6-dioxy 2,2-dimercaptochrome _4_yl)-indole_methyl-valetite xanthine mp 204-206 · C. b) take 0.45 g (1·5 house Moule) The above compound was dissolved in 5 ml of DMF and added dropwise to a solution of 50 mg (1.6 mmol) of 80% sodium hydride in 2 ml of DMF. After 2 hours at rt, 0. 27 g (1.6 mmol) of 1-iodopropane was added and the mixture was stirred at rt for 2 days. After operation and recrystallization from isopropanol, 〇·22g (土)_反_Ν_(6-propoxy-3_hydroxy-2,2-diindolyl-4-yl)_Ν·曱Base-oxime sulfonamide; m_p.l49_15rc. Example 9: N-(6·propoxy-2,2-dimethyl-2H·chromenyl-methylene)-N-methyl·sulfonamide (Please read the back note first and then fill out this page)

Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs

〇"V a) Take 3.3 g of (±)-trans (6-+oxy-3-ethenyloxy-2,2·diindolyl-4-yl)indolyl-methylglucamine ( Example 2) nitriding in the presence of pd/c, yielding 2.6 g (earth) · anti (6 · warthenyl-3-ethyl-45-

This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 593307 A7 B7 V. Description of invention (44) Oxy-2,2-dimethylchroman-4-yl)-N-methyl- Sustained amine; mp 172-174, C. b) Next, similar to Example 7, reacted with DBU in toluene, after chromatographic chromatography and recrystallization from hydrazine/EA, yielding 1.2 g of N-(6-hydroxy-2,2-dimercapto-2H- Chromen-4-yl)methyl-methanesulfonamide, mp 13 (M32 ° C. c) Similar to Example 8b, from 0.5 g of N-(6·hydroxy·2,2-dimercapto-2H·chromene Alkylation of 4-yl)-fluorenyl-hydrazinamide with 1-iodopropane yields 0.36 g of Ν-(6-propoxy-2,2-diindolyl-2-indole-4- Base)-Ν-methyl: Methionamide mp 93-95 · C. Example 10··(土)-反-N-(6-benzyloxy-3-hydroxy-2,2·diindolyl·4-yl)-indole-butyl·Rich amine (please read first) Note on the back and fill out this page)

a) (soil)-anti-Ν· (6-decyloxy-3-carbyl- 2,2-diindole-containing 4-yl)---------------------------- Take 0.47 g (16 mmol) of 80% sodium hydride, 1.75 g (18 mmol) of sulfonamide and 4.0 g (14 mmol) of 6-benzyloxy-2,2-didecyl- The 25 ml DMSO reaction mixture of 3,4-epoxy full (Example If) was heated at 50 ° C for 36 hours. The reaction mixture is poured into ice water-46- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 593307 A7 B7 V. Inventive Note (45), suction filtration of precipitated product from isopropanol / Recrystallization from petroleum ether gave 2.9 g of the title compound mp 181-182. b) A solution containing 1.0 g (2.6 mmol) of the above compound and 90 mg (2.99 mmol) of 80% sodium hydride in 1,3-ml of DMF was stirred at RT for 1 hour, 0.51 g (2.8 mmol) Ear) 1-iodobutane, all heated at 50eC for 10 hours. The reaction mixture was concentrated under reduced pressure and the residue was evaporated and evaporated. Purified by gel chromatography using cyclohexane/EA3:1 to yield 0.5 g (soil)-trans-N-(6-benzyloxy_3_hydroxy-2,2-dimethylchroman-4-yl ) _N-butyl sulfonamide, mpl59-160eC. Example 11: N_(6-benzylindole-2,2·didecyl-2H-chromen-4-yl)-N-indenyl-indolesulfonamide (Please read the back note first and then fill out this page )

The Ministry of Economic Affairs Central Bureau of Standards and Staff Employees Cooperatives printed methods similar to Examples 2 and 4, consisting of (±)-trans-indole-(6-benzyloxy-3-hydroxy-2,2-diindolyl-4-yl) The compound was obtained from mp-yt-sulfonamide (Example 10) mp 74-76 °C. Example 12·· (±) _--N-[(6-Benzyloxy-3-hydroxy-2,2-diindolyl-4-yl)-methanesulfonylamino]methyl acetate-47- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ^307 ^307

, invention description (46

. ^0 oxy-3-hydroxy-2,2-diindolyl-4-yl)-methanesulfonamide (Example 1〇a) was alkylated with ethyl bromoacetate to give 〇·5 g (soil)- Inverse (6-octyloxy-3-hydroxy-2,2-dimercaptochroman-4-yl)-methanesulfonylamino]acetic acid hydrazine 5, mp 133-135 °C. Example 13···(±)-trans-N-[3-hydroxy-2,2-dimethyl(4,4,4,trifluorobutoxy)-chroman-4-yl]-N-A Base - Acetoamine (please read the notes on the back and fill out this page)

Order a) (±)-County [3,6-dihydroxy-2,2-dimethyl)chrome _4_yl] decyl-methanesulfonamide 2.0 g (5 mmol) ±) n (6-benzyloxy dimethyl dimethyl chroman-4-yl) fluorenyl-methanesulfonamide (example 〇 under normal pressure in 200 ml THF / methanol (1:1), Hydrogenation in the presence of palladium/activated carbon (5% Pd) until the absorption of hydrogen ceases. The catalyst is filtered off and the mixture is concentrated to yield 1.2 g of product, mp 198-202 b) 〇·7 g (2.3 mmol) Ear) (earth)-anti-N_[3,6-dihydroxy·-48- This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) P. Economy, Printed by the Central Bureau of Standards Staff Consumer Cooperative 593307 A7 B7 V. Inventive Note p) 2,2-dimercapto)chroman-4-yl]_N-mercapto-sulfonamide 8 ml of DMF solution containing 64 mg (2.7 mmol) 80% Sodium hydride in 6 ml of DMF solution. After 1 hour, 0.56 g (2.4 mmol) of 4,4,4-trifluoroethyl iodide was added and the mixture was stirred at RT overnight. The reaction mixture was concentrated and concentrated, and the residue was extracted with EA and water, and purified by silica gel chromatography to yield 0.71 g (±) _---N-[3-hydroxy-2,2-didecyl-6- (4,4, 4-trifluorobutoxy)-chroman-4-yl]decyl-nonylsulfonamide, mp 161-163·0 Example 14: (earth)-trans-purine-(6-butoxy-3- Hydroxy-2,2-dimercaptochroman-4-yl)-indole-ethyl-anthracene amine (please read the notes on the back and fill out this page)

The Employees' Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed a similar example 5e from 6-butoxy-2,2-dimethylchroman-3,4-epoxy (Figure 5d) and ethyl-sulfonium sulfonate. The amine is prepared from the amine. After chromatographic chromatography using dichloromethane/furfuryl alcohol 97:3, the title compound was isolated, mp 39-14 (TC. Example 15: N-(6-butoxy-2,2-didecyl-2H- Chromene 4-yl)-N-ethyl-methanesulfonamide-49- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X29? mm)

593307 A7 -_______B7 V. Description of invention (48)

ί V This compound was formed as a by-product in the preparation of the compound of Example 14, and was isolated in the chromatographic method described therein, the lowest polarity part, mp 68_70eC 〇 Example 16: (3S 4S)- (-) -N_(6-butoxy-3-hydroxy-2_diindolyl-4-yl)-N-mercaptomethyl decylamine (please read the back of the note first and then fill out this page)

Order a) (3S, 4S)- (-) -6 · Butoxy-2,2-dimercapto-3,4·Epoxy Colors Ministry of Economics Central Bureau of Standards Staff Consumer Cooperatives printed under (TC, Take 76 ml (42 mmol) of 〇·55Μ sodium hypochlorite solution, adjust to pH 11.3 with disodium hydrogen phosphate, and add to 4.6 g (20 mmol) of 6-butoxydiindenyl-2H-chromene ( Example 5b) with 〇·5 g (0·8 mmol) (S,S) - ( + ) -N,N, bis-. (3,5-di-t-butyl ylidene) 1,2_diaminocyclohexane manganese (III) gas (Jacobsen's catalyst) in 20 ml of di-methane solution, the reaction mixture was stirred vigorously for 3 hours, _ -50- The paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm 1 " 593307 A7 ________B7 _ V. Inventive Note (49) From the organic phase, the aqueous phase is extracted twice with dioxane. The crude product is cyclized. /EA 9:1; ^ gel chromatography, yielding 1 · 6 g (3S ' 4S)-(-) -6-butoxy-2,2-didecyl·3·4_ epoxy color; Optical rotation -14.9 · (C = 0.6, sterol) b) Similar to Example 5e, from 1 gram (3s, 4S) - (-) -6-butoxy-2, 2- Base-3,4_epoxy full yield 〇·7 g (3S,4R) - (-) -N-(-6-butoxy-3-hydroxy_2,2_dimethylchroman-4 -yl)-N-mercaptosulfonamide, mpl52-154eC; optical rotation -9·9· (C=0.5, sterol). Example 17: (3S,4R) - (-) -NC-6- Benzyloxy_3_hydroxy-2,2-dimethylchroman-4-yl)·Ν-mercapto-ethanesulfonamide (please read the notes on the back and fill out this page)

Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs a) (3S, 4S)-6-Benzyloxy-2,2-dimercapto-3,4-epoxy color similar to Example 16a, from 5.0 g of 6-benzyl Oxy-2,2-dimethyl-2oxime-chromene (Example Id) yielded 2.3 g of a palmitic epoxide. b) from 1·0 (37 mmol) (3S, 4S)_6_benzyloxy-2,2-dimethyl-3,4-epoxy full, 1.45 g (74 mmol) N- Mixture of methyl _ N-trimethyl decyl ethane sulfonamide with 1.17 g of tetrabutylammonium fluoro trihydrate (37 house Moule), heated at 6 〇 · c 15 • 51 - paper scale Applicable to China National Standard (CNS) A4 specification (21〇χ297 public celebration) --- 593307 A7 B7 V. Description of invention (50) hours. The solvent was removed by distillation, the residue was separated on a hydrazine column, and the product was recrystallized from isopropyl alcohol. Yield 0.4 g (3S,4R) - ( + ) · Ν-(-6-benzyloxy-3-hydroxy-2,2-dimercaptochroman-4-yl)methylethanesulfonamide, mpl72-174 'C, optical rotation -40.8*C. Example 18: ( 3R,4S ) - ( + ) -N-[3-Pyano-2,2-dimercapto-6_(4,4,4-trifluorobutoxy)chroman-4-yl Mercapto-ethanesulfonamide

F ·· -------------- (Please read the notes on the back and fill out this page)

A) Similar to Example 17a, but with (R,r) - ( + ) -n,n,·bis(3,5-di-t-butyl-salicylidene)-1,2-diamine The cyclohexane manganese (m) gas is obtained as (3R,4R)-6' nokilyl-2,2-dimercapto-3,4-epoxy. b) (3R,4S) - (+) (6-Benzyloxy_3_hydroxy-2,2-dimethyliso-4-yl)-N-methyl-ethyl decylamine added 3.7 g (13 mM) (3r, 4R) -6-benzyloxy-2,2-dimercapto-3,4-epoxy full 6·5 ml DMS 〇 solution to 21 g (17 mmol) Ear) N-mercapto-ethanesulfonamide with 0.2 g (6.7 mmol-52- This paper scale applies to Chinese National Standard (CNS) A4 specification (210x297 mm) -. Printed by the Ministry of Economic Affairs Central Bureau of Standards Staff Consumer Cooperative 593307 Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives, Printing A7 B7 V. Inventions 1 ear) 80% hydrogenated 6.5 ml DMS 〇 solution, the mixture was heated at 6 ° C for 20 hours. The reaction mixture was poured into 3 mL of water and the product was filtered with suction. Purification by cyclohexane gel chromatography using cyclohexane 8·2 yielding 1.9 g (3R,4S) - (+) (6-octyloxy_3_hydroxyl

Base-2,2-dimethylchroman-4-yl)-N-methyl-ethanesulfonamide, mpl65_ 167.C c) (3R,4S) - ( + ) -N- (3,6- Dihydroxy-2,2-dimercaptochroman-4-yl)-N-methylethylamine was similar to Example 13a. After hydrogenation of 1.7 g of the above benzyl ether afforded 1.3 g of the title compound. A similar example to 131^, from 1.15 g (311,48)-( + )_:^-(3,6-dihydroxy-2,2-dimethylchroman-4-yl)-N-fluorenyl-B After the sulfonamide is cleaved with 4,4,4-trifluorobutyl, 1.1 g of (3R,4S)-(+)-N-[3-hydroxy-2,2-dimethyl-6- ( 4,4,4·Trifluorobutoxy)chromanyl]-N-methyl-ethanesulfonamide, mpl73-174eC, optical rotation +20·9·. Example 19: ( 3R,4S ) _ ( + ) benzyl-2,2-dimethyl-6-(4,4,4-trifluorobutoxy)chroman-4-yl]-Ν_甲Base-sulfonamide

(Please read the notes on the back and fill out this page) it 593307 Ministry of Economic Affairs Central Bureau of Standards Staff Consumer Cooperatives Print A7 B7 V. Inventions (52) a) 6- (4,4,4-Trifluorobutoxy 2,2,2-dimethyl chroman-4-one is added dropwise with 13.4 g (70 mmol) of 2,2-dimethyl-7-hydroxychroman-4-one (example la) 250 ml of DMF solution was added to a solution of 2.65 g (88 mmol) of 80% sodium hydride in no ml of DMF. The mixture was stirred at RT for 1 hour. 14.6 g (76 mmol) of 4,4, each trifluorobutyl bromide was added and the mixture was allowed to stand at RT overnight. The reaction mixture was poured into 3 liters of water and allowed to stand overnight. Aspirate and filter the sediment, wash the strip with water, and dry under reduced pressure. 20.0 g of 6-(4,4,4-trifluorobutoxy)_2,2-dimethylchroman-4-indole b) 6-(4,4,4-trifluorobutoxy)-2 , 2-dimethylchromanol contains 20 g (66 mmol) of 6-(4,4,4·trifluorobutoxy)_2.2-dimethylchroman-4·one and 2.5 g ( 66 millimoles) sodium borohydride 1 曱 曱 授 授 授 授 。 。 。 。 。 。 。 。 。 。 。 The reaction mixture was poured into ice water, mixed with ordinary salt, and extracted four times with EA. The organic phase was dehydrated and concentrated to give 19.5 g of 6-(4,4,4-trifluorobutoxy) 2,2-dimethylchroman-4-ol. c) 6-(4,4,4-Trifluorobutoxy) broad 2,2-dimethyl-2H-chromene containing 19.5 g (64 mmol) 6_ (4,4,4-trifluoro A solution of butoxy)-2.2-dimercaptochroman-4-ol in 200 ml of toluene was mixed with 2 g of p-toluenesulfonic acid monohydrate and heated at 10 °C for 21⁄2 hours. After cooling, the whole was extracted twice with each 120 ml of sodium hydrogencarbonate solution, and stirred with activated carbon. Filtration and concentration under reduced pressure gave 16.7 g of 6-(4,4, 'tris-butoxy)-2,2-dimethyl-2H-chromene. -54- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) (Please read the note on the back and fill out this page) ϋ-i In n.. Printed by the Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives System W307

d) (3R,4R) _6·(4,4·4-trifluorobutoxy)-2,2-dimethyl-3,4-nuclear oxygen color at 〇°C, take 38·5 ml (22 mmol) 〇·55 μ sodium hypochlorite solution, adjusted to ΡΗ11·3 with disodium hydrogen phosphate, and added dropwise to 2.86 g (10 mmol) of 6_(4,4,4-trifluorobutoxy)- 2,2-Dimethyl-2Η·chromene and 〇.26 g (〇·4 mmol) (R,R) - (-) -Ν,Ν,-double (3,5-di-third Butyl hydrazide) 丨, 2_diaminocyclohexane manganese (III) mutated (Jac〇bsen, s catalyst) in U ML solution. Stir vigorously for 3 hours, separate the organic phase, and extract the aqueous phase with a small amount of dichloromethane. The organic phase was filtered through a short-purchase column to remove the catalyst, and the appropriate solvent was concentrated under reduced pressure to give 1.65 g (3R, 4R) - ( + ) -6- (4,4,4_Trifluorobutoxy)-2,2-dimethyl-3,4-epoxy full waxy solid; optical rotation about + 13 ° C (00.5; 曱Alcohol) e) Under argon, add 77 g (7.11 mmol) of N-methyl-methanesulfonamide to 3 ml of DMSO containing 0.065 g (2.7 mmol) of 80% sodium hydride. In suspension, It was stirred at RT 2〇 min. 1.65 g (5.5 mmol) of (3R,4R)-( + ) -6-(4,4,4-trifluorobutoxy)-2,2-dimercapto-3,4-ring was added dropwise. The solution was filled with 5 ml of DMSO in oxygen, and all were allowed to stand at RT for 4 days, and then heated at 45 ° C for another 9 hours. The mixture was poured into water, and the precipitate was filtered under suction, and dried thoroughly under reduced pressure to yield 1.9 g of (3R,4S) - ( + ) -[3-hydroxy-2,2-dimethyl-6- (4,4, 4-Trifluorobutoxy)chroman _4_yl]-N-mercapto--55- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) (please read the precautions on the back) Fill in this page)

593307 A7 B7 V. INSTRUCTIONS (54) Sulfonamide, recrystallized from a small amount of isopropanol (> 1.4 g; mpl 78 179 eC, optical purity (p. HPLC) 100%). Example 20: (3S,4R) _ (-) Hydroxy-2,2-dimercapto-6-(4,4,4-trifluorobutoxy)chroman _4·yl]decyl·methylsulfonate amine

F

Similar to the method of Example 19, but instead (s, S) - (-) - Ν, Ν, - bis-(3,5-^ - " second butyl sulfoxide)-1,2- The amine-based bad burned (ΠΙ) gas is used as an epoxidation catalyst, mpl 79 ° C, optical purity (ply HPLC) 100%. Example 21: (earth)-trans-N-[3-acetoxy-6-(4,4,4-trifluorobutoxy)-2,2-diindolyl-4-yl]fluorenyl - 曱 醯 醯 ! 卜 卜 卜 卜 卜 卜 请 请 请 请 请 请 请 请 请 请 请 请 请 请 请 请 请 请 请 请 请 请 请 请 请 请 请 请

Similar to Example 2, consisting of 3.5 g (soil)-trans-N-[3-hydroxy-2,2-dioxin-56- This paper scale applies to Chinese National Standard (CNS) Α4 specification (210X297 mm) 593307 A7 B7 , inventive description h base _6_ (4,4,4_trifluorobutoxy). chromophoric {yl]- hydrazine_methyl _ continual amine (example 13) with 28 ml of acetic anhydride in 55 ml of pyridine In the process, 3.7 g (±)-trans-indole-[3·acetoxy-bu (4,4,4-trifluorobutoxy)_ 2,2-dimethylchroman-4-yl] was produced. - Ν-methyl-methanesulfonamide, mpl 〇 6.c. Example 22: N_[6·(4,4,4-tris-butoxy)_2,2-dimethylisophthalen-4-yl]-N-methyl-methyl decylamine

Printed by the Consumer Standards Agency of the Central Bureau of Standards of the Ministry of Economic Affairs - 丨丨卜丨丨—#—(Please read the notes on the back and fill out this page) Take 3.5g (±)-anti-team [3-acetoxy -6-(4,4,4-Trifluorobutoxy)-2,2-methylchroman-4-yl]methyl-methyl decylamine (Example 21) and 6.8 g of DBU in 30 mL of toluene The solution was heated at 1 〇 5 · c for 20 hours. The reaction mixture was diluted with EA and washed with hydrochloric acid until the aqueous layer was acid. The mixture was washed with a solution of nitrosamine solution, dehydrated by sulphuric acid, concentrated in vacuo and triturated with glucan to give 1·7 g of 1^-[6-(4,4,4-trifluorobutoxy)-2. 2-Dimercapto-2Η-chromen-4-yl]indolyl-methanesulfonamide, mpll8eC. Example 23: (3R,4S)-{[3·Hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy)chroman-4-yl]-indolesulfonamide }}Acetyl acetate 57- This paper scale applies to China National Standard (CNS) 8% 4% (210X297 mm) A7 B7

593307 a) (3R,4S)-N-[3-Carbo- 2,2-didecyl-6-(4,4,4-trifluorobutoxy)chroman-4-yl]曱The amine was added under argon with 0.82 g (8.6 mmol) of methanesulfonamide to a suspension of 0.2 g (6·6 mmol) of 80% sodium hydride in 3.5 ml of DMSO and the mixture was stirred at RT for 30 min. . Add 2·〇克(6.6 mmol) (3R,4R ) _ ( + ) -6- ( 4,4,4_ trifluorobutoxy)_2,2_didecyl·3,4_ ring A solution of 6 ml of DMSO in oxygen (Example i9d) was heated at 60 ° C for 20 hours. The mixture was poured into water, the precipitate was filtered off with suction, and dried thoroughly under reduced pressure to give <RTI ID=0.0>> 4-Trifluorobutoxy)chroman-4-yl]methanesulfonamide, mpl86*C. b) A solution containing 0.5 g (1·3 mmol) of the above compound in 5 ml of DMF with 5 g of sodium hydrazine (17 mmol) in sodium hydride was stirred at RT for 1 hour. 0. 2 g (1.3 mmol) of methyl bromoacetate was added and the mixture was stirred at RT overnight. After purification by operation and gelatin chromatography, 〇·2 g (3R, 4S ) - { [3. thiol-2,2-dimercapto-6-(4,4,4-tri-n-butyl) - Chromium-4-yl]methionite amino}acetic acid vinegar. Example 24: ______-58-________ This paper scale applies to the Chinese National Standard (CNS) Α4 specification (210Χ297 mm) " ' — :±|_:1#-----11 订 ------, -r VC Please read the notes on the back and fill out this page.} Department of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives, Printed 593307 A7 Ministry of Economic Affairs, Central Bureau of Standards, Staff Consumer Cooperatives, Printing and Invention Instructions (57) Similar to the above methods, the following can be prepared Compounds of a definite importance: a) anti-Ν·[3-hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy)chroman _ 4_yl]-Ν · ethyl sulfonamide; b) trans-hydrazine-[3-hydroxy-2,2-dimercapto-6-(4,4,4-trifluorobutoxy)chroman-4-yl]- Ν_(2,2,2-trifluoroethyl)methyl decylamine; c) trans-Ν-[3·hydroxy-2,2·dimethyl_6-(4,4,4-trifluorobutoxy Base) color full _ 4-yl]-Ν·propyl sulfonamide; d) trans-Ν-[3-carbyl-2,2-dimethyl·6· (4,4,4-trifluoro Butoxy group, full color _ 4-yl]-fluorene-ethyl methylamine, e) anti-purine-[3-carbyl-2,2-dimethyl-6- (4,4,4 -Trifluorobutoxy)-chroman-4-yl]-indole-(2,2,2-trifluoroethyl)ethanesulfonamide; f) anti-purine-[3-carbyl-2,2 -dimethyl -6-(4,4,4-trifluorobutoxy)chroman-4-yl]-indole·propyl ethoxylate, g) trans-Ν-[3-hydroxy-2,2-di Methyl-6-(3,3,3-trifluoropropoxy)chroman-4-yl]-indole·methyl hydrazine, h) trans-Ν-[3-hydroxy-2,2- Dimethyl-6-(3,3,3-trifluoropropoxy)chroman-4-yl]-indole-ethylsulfonamide; i) anti-purine-[3-hydroxy-2,2 - dimethyl-6-(cyclopropyl decyloxy)chromate _4_ yl]-oxime-methylmethanesulfonamide; j) anti-Ν-[3-hydroxy-2,2-dimethyl- 6-(cyclopropylmethoxy)chroman _4_ ki]-Ν_methylethanesulfonamide; Medical Experiment-59- This paper scale applies to Chinese National Standard (CNS) Α4 specification (210X297 mm) (please Read the notes on the back and fill out this page.) β Γ 593307 The Central Bureau of Standards of the Ministry of Economic Affairs, the Consumer Consortium, prints A7 B7. V. Description of the Invention “) The Isk channel from human, mouse or guinea pig in Xenopus egg cells. In order to isolate the egg cells from Xenopus laevis, the sister removes the follicles, and then the RNA encoding Isk synthesized in the test tube is injected into the eggs. After the Isk protein is expressed for 2 to 8 days, two micro-electrons are used. The extreme voltage splint technique measures Isk current in egg cells. At this time, the isk channel is usually activated by using a voltage of up to -10 mV for 15 seconds. A solution containing the following components was injected into the culture tank: NaCl 96 mM, KCl 2 mM, CaCl 2 1.8 mM, MgCl 2 I mM, HEPES 5 mM (pH 7.5 was titrated to 7.5). These experiments were performed at room temperature and data were obtained and analyzed using the following instruments: Geneclamp Amplifier (Axon Instruments, Foster Coty, USA): MacLab D/A Converter and Software (Australian AD) The instrument company (AD Instruments, Castle Hill, Australia). The substance according to the invention is added to the culture solution according to different concentrations for the test. The effect of the substance is calculated as the percentage inhibition of the Isk control current when no substance is added to the solution. This data was extrapolated using the Hill equation to obtain the inhibitory concentration of each substance ις50. References: AE Busch, H.-G. Kopp, S. Waldegger, I. Samarzija, H. SQBbrich, G. Raber, K. Kunzelmann, JP Ruppersberg and F. Lang; "Inhibition of both exogenously expressed lsK and endogenous K+ channels in Xenopus oocytes by isosorbide dinitrate"; J. Physiol. 491 (1995), 735-741; T. Takumi, H. Ohkubo and S. Nakanishi; "Cloning of a membrane protein that induces a slow voltage-gated potassium current"; Science 242 (1989), 1042-10 45; L______-60-___ This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) (Please read the note on the back and fill out this page) 593307 A7 B7 ^ Invention description) MD Varnum, AE Busch, CT Bond, J. Maylie and JP Adelman; "The minK channel underlies the cardiac potassium current and mediates species-specific responses to protein kinase"; C. Proc. Natl. Acad. Sci. USA 90 (1993), 11528 The IC5Q value of the compound according to the present invention was determined by the above method using the human Isk protein as follows: The Central Bureau of Standards Bureau of the Ministry of Economic Affairs, the Consumer Consortium, printed the integrator IC-50 _ Example 1 0.2 Example 2 13 Example 3 6.5 Example 4 1.6 Example 5 0.25 Example 6 > 10 Example 7 1.6 Example 8 0.9 Example 9 2.6 Example 10 0.4 Example 11 1.6 Example 12 0.8 Example 13 0.2 Example 14 0.2 Example 15 - 1.3 Example 16 0.4 Example 17 0.4 Example 18 0.1 Example 19 0.1 Example 20 0.4 Example 21 ~10 Example 22 0.6 Example 23a 1.7 -61- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please Read the notes on the back and fill out this page. Γ i

Claims (1)

593307 A8 B8 C8 D8 VI. Patent Application No. 87118010 ROC Patent Appln. No. 87118010 Text of the patent application without amendments after the amendment - Annex (II) Amended Claims in Chinese - Enel. (U) ( March 5, 1993, Republic of the United States (Submitted on March ζ, 2004) 1. A compound of formula I 〇〇N ^ R(6) R(2) R(D Printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs, where the R(5) attachment is marked as one of the 5, 6, 7 and 8 positions, and where R(1) and R(2) respectively Is Cw alkyl; R(3) is Cw alkyl; R(4) is CM() alkyl, CF3-CM alkyl or Cm alkoxycarbonyl CM alkyl; R(5) is CMG alkoxy, benzyl Oxy, CF3-CM()alkoxy or C3_7 cycloalkyl Cm alkoxy; R(6) is hydrogen, hydroxy, Cm alkoxy or OCO(R10d); R10d is argon or has 1, 2 or 3 a carbon alkyl group; B is hydrogen; or R (6) and B together form a bond; and its physiologically tolerable salt. This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 87397B-connected 1 593307 Six Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A8 B8 C8 D8 Patent application scope 2. According to the scope of patent application No. 1 A compound of formula I, wherein: R (1) and R (2) are each a Q 6 alkyl group; R (3) is a C w alkyl group; R (4) is a C w alkyl group, a CF 3 -C m alkyl group or a C m alkoxycarbonyl C m alkyl group; R(5) is CN8 alkoxy, benzyloxy, CF^Cw alkoxy or C3_7 cycloalkyl Ci_4 alkoxy; R(6) is hydrogen, hydroxy, Cm alkoxy or OCO(RlOd); R10d It is hydrogen or an alkyl group having 1, 2 or 3 carbons; B is hydrogen; or R(6) is a bond with B; and a physiologically tolerable salt thereof. 3. A compound according to claim 1 or 2 wherein R(5) is attached at the position of the label 6, that is, the compound of the formula la·· la wherein R(l), 11(2), 11(3 ), 11(4), 11(5), 11(6) and 3 are as defined in claim 2; and physiologically tolerable salts thereof. 4. A compound of formula I according to claim 1 of the scope of the patent, wherein: R(l) and R(2) are respectively Cw alkyl; -63 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 593307 A8 B8 C8 D8 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing patent application scope R (3) is Cw alkyl; R (4) Is Cw alkyl, CF^Cm alkyl or Cm alkoxycarbonyl Cm alkyl; R(5) is Cm alkoxy, benzyloxy, CF^Cw alkoxy or C3_7 cycloalkyl Cm alkoxy; R (6) is a hydroxyl group; B is a hydrazine; or R(6) is a bond with B; and a physiologically tolerable salt thereof. 5. A compound of formula I according to claim 1 wherein: R(1) and R(2) are methyl; R(3) is Cw alkyl; R(4) is Cm alkyl, CF3-CM alkyl or Cm alkoxycarbonyl Cm alkyl; R (5) is Cm alkoxy, benzyloxy, CF^Cw alkoxy or (: 3_7 cycloalkyl C1 _ alkoxy; R (6) and B together a compound of the formula I, wherein: R(1) and R(2) are fluorenyl; 3) is Q.2 alkyl; R( 4) is Cm alkyl, CF^Cm alkyl or Cm alkoxycarbonyl Cm alkyl; R(5) is Ci_6 alkoxy, benzyloxy, CF^Cw alkoxy or C3_7 ring-64- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 593307 VI. Patent application scope Printed by the Intellectual Property Office of the Ministry of Economic Affairs, A8 B8 C8 D8 alkyl Cm alkoxy; R (6) is a hydroxyl group; B is hydrogen; and its physiologically tolerable salt. 7. A method of preparing a compound of formula I according to one or more of claims 1 to 6 of the patent application, which comprises a) a compound of formula II (4) Wherein R(1), R(2), and R(5) are as defined in claims 1 to 6 of the patent application, and are reacted with a sulfonamide of the formula III, wherein R(3) and R(4) are as claimed Included in the scope of items 1 to 6 and the oxime is chlorine or a metal equivalent or a trialkane group, forming a formula lb of a full alcohol; or b) from a compound of formula lb in a manner known per se, in a burnt or deuterated form In the reaction, it is reacted with a formula R(10d)-L alkylating agent or a formula R(10d)-COL oxime or a formula (R(10d)-(CO)2O anhydride, wherein R(10d) is as claimed in the patent scope A definition of 1 to 4 and L is a nucleon-away group, which produces a compound of formula Ic, wherein R(6) is OR(l〇d) or OCOR(lOd); -65 - the paper scale applies to Chinese national standards ( CNS) A4 size (210x297 mm) 593307 A8 B8 C8 D8 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing VI. Application for patent scope R(4)〇, s· Or c) from the compound of formula Ic R(4) 〇v -R(3) R(6) R(2) R(1) •R(3) R(6) R(2) R(1) -R(3) R(4) 〇 NT ;S* R(2) R(1) 8. wherein R(l), R(2), R(3), R(4) and R(5) are as defined in claims 1 to 6 and R (6) is OCOCH3, which is converted into a compound of formula Id in an elimination reaction, wherein R(l), R(2), R(3), R(4) and R(5) are as disclosed in claims 1 to 6 The definition in . A pharmaceutical composition for treating and preventing a K+ channel modulating disease, comprising an effective amount of at least one compound of formula I according to one or more of claims 1 to 6 and/or physiologically tolerable thereof Subject to 66 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210x297 mm). 593307 A8 B8 C8 _D8__ VI. Scope of Application The salt is used as the active compound and pharmaceutically acceptable excipients and additives. 9. A compound of formula I according to claim 1 of the scope of the patent application, which is a medicament which has a function of blocking the K+ channel and is useful for the treatment and prevention of diseases mediated by K+ channels. 10. A compound of formula I according to claim 9 of the patent application, which is a medicament for inhibiting gastric acid secretion. 11. A compound of formula I according to claim 9 of the patent application, which is a medicament for the treatment or prevention of ulcers in the stomach or intestines. 12. A compound of formula I according to claim 9 of the scope of the patent application as a medicament for the treatment or prevention of reflux esophagitis. 13. A compound of formula I according to claim 9 of the scope of the patent application, which is for use as a medicament for the treatment or prevention of diarrhea. 14. A compound of formula I according to claim 9 of the scope of the patent application, for use as a medicament for the treatment or prevention of all types of arrhythmia, including atrial, ventricular and upper ventricular arrhythmia. Printed by the Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative 15. The compound of formula I according to item 9 of the patent application is used as a medicine for treating or preventing arrhythmia which can be eliminated by prolonging the action potential. 16. A compound of formula I according to claim 9 of the scope of the patent application, for use as a medicament for the treatment or prevention of atrial fibrillation or atrial flutter. : 17. A compound of formula I according to claim 9 of the scope of the patent application, which is used as a medicament for the treatment or prevention of re-entry into arrhythmia or prevention of sudden cardiac death due to ventricular fibrillation. -67 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 593307 A8 B8 C8 D8 VI. Patent application scope 18. According to the formula I, the compound of formula I of claim 9 is used as It is used to treat drugs with insufficient heart function, especially congestive heart failure. ♦ Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 8 6 This paper scale applies China National Standard (CNS) A4 specification (210x297 mm) 593307 No. 87118010 patent application pharmacological experiment supplement description: February 1990 L Diseases in the Gastrointestinal Region The compounds of formula I of the present invention have been tested to demonstrate blocking activity against cAMP-activated large intestinal L-channels. Using the experiment described in Reference 1, the following IC5G values can be obtained. Example No. IC50 (slurry side) [μΜ] 1 0.27 2 > 10 3 12.9 4 3.6 _ 5 0.18 6 3.6 7 0.9 8 0J6 10 4.8 The data discussed in the literatures 2, 3, 4, and 5's are sufficient as evidence for the treatment of the above compounds to treat He and Ai Lin under the stomach. Secondly, the potassium slaves that have been discussed in reference 6 are also important for gastric acid secretion. avengh87397. Pharma-ch 593307 is sufficient to support the use of the blockers to inhibit gastric acid secretion and to treat gastric reflux and gastric ulcer. 4 Dedicated 8 9 and 1 also describe similar potassium channels that are important for pancreatic function. Thus, the blockers disclosed in this case can be used to treat acute otitis. 2. Cardiovascular disease This case is on pages 30 to 32 of the manual (pages 22 to 23 of the English manual). Iks is resistant to the silk. It is suitable for the silk. The domain is for the side of the literature. 0 Fluttering compound 19 stops the atrial fiber. Fibrillation/Atrial Test Example 19 Compound vs. Axis/Heart__, with a right heart anti-surgical lesion and a rapid atrial rhythm triggering atrial atrial arrhythmia. 'Compound 19 (3mg/kgi V ) has been discontinued in u animals, atrial fibrillation / flutter, and repaired sinus rhythm (63.6%) in the w machine (25.3-26.8% extension) and non-replacement In the flow machine (丨7 〇_23 2% extension), the rate of atrial non-response (ERP) was delayed in a rate-independent (neutral rate-dependent) method. Not ^ T shell defense all animals tested for rapid rhythm immediately Dandu room flutter 'also continued in the non-converter extension of the atrial. Decrease avcnghK7107 plumn«-ch -2- 593307 The center time of atrial flutter is 73 minutes. Accordingly, the compound of Example 19 showed efficacy against atrial fibrillation/atrial flutter in pigs. Extending the ventricular effective non-response period (ERp) between pigs and dogs with compound 19: ventricular anti-rhythmia effect in dogs and pigs anesthetized at 120, 140, 180/min and 100, 140, 180/min, respectively A study of the efficacy of Compound 19 (1 mg/kg i.v.) on ventricular non-response was performed. The ventricular erp extended by compound 19 is not associated with the rhythm of the heart (neutral rate). In pigs, ventricular ERP was prolonged by 35 3_39·8% (range of different rates). In dogs, prolonged to 16β9_22·7% of baseline ERP. Accordingly, the compound 19 greatly prolongs the ventricular non-response, which is sufficient for confirming the anti-arrhythmia effect. Reference 11 further provides evidence of the suitability of Compound 19 for the treatment of cardiovascular disease, and a clinical discussion therein, wherein the compound designated "“%," is the compound of Example 19 of the present invention. avc'n^hK / \%)Ί pharina-ch 593307 1. ) E. Lohrmann, I. Burhoff, RB Nitschke, HJ Lang, D. Mania, HC Englert, M. Hropot, R. Warth, W. Rohm, M. Bleich, and K Greger. A new class of inhibitors of cAMP-mediatcd CV secretion in rabbit colon, acting by the reduction of cAMP-activatedK+ conductance. 429:517-530, 1995. 2. ) D. Ecke, M. BIcich, E. Lohrmann , M. Hropot, HC Englert. HJ Lang, R. Warth, W. Rohm, B. Schwartz, G. Fraser, and R. Greger, A chromanol type of K+ channel blocker inhibits forskolin- but not carbachol mediated Cl- secretion in Cell and L1 colon. Cell Physiol Biochem 5:204-210, 1995. 3. ) R. Warth, N. Riedemann, M. Bleich, W. VanDriessche, AE Busch, and R. Greger. The cAMP-regulated and 293B inhibited K+ conductance of rat colonic crypt base cell s. Pflugers Arch 432:81-88, 1996. 4. ) M. Mali, M. Bleich, M. Schtirlein, J. Ktihr, Η, H. Seydewitz, M. Brandis, R. Greger, and K. Kunzelmann. Cholinergic ion secretion in human colon requires coactivation by οΑΜΡ,^.7.ΡΛν5·/^/. 275:G1274-G12815 1998. * 5. ) K. Kimzelmaim, M. Hixbner, R. Schreiber, R. Levy-Holzman, H. Garty, M. Bleich, R. Warth, M. Slawik, T, von Hahn, and R. Greger. Cloning and function of the rat colonic epithelial KVLQT1 (KCNQ1). J Biol Chem submitted, 2000. 6. ) F Grahammer, AW Herling, HJ Lang, A Schmitt-Graff, O, Wittekindt, R. Nitschke, M. Bleich, J. Barhanin, and R. Warth, The cardiac K+ channel KQsTQl is essential for gastric acid secretion. 7.) Raraty M, Ward J, Erdemli G. Vaillant Cs Ncoptolemos JP. Sutton R? Petersen OH. Calcium-dependent enzyme activation and vacuole formation in the apical granular region of pancreatic acinar cells. Proc Natl Acad Sci USA. 2000 Nov 21;97( 24): 13126-13131. 8.) SJ Kim, G. Kerst, R. Schreiber, H. Pav Enstadt, R. Greger, MJ Hug, and M. Bleich. Inwardly rectifying K+ channels in the basolateral membrane of rat pancreatic acini, PfltigetsArchinpKss9 2000. 9. ) SJ Kim, A. Zdebik, JK Kim, R. Nitschke, M. Bleich , A. Schmitt-Graff, J. Barhanin, R. Greger, and R. Waith. The role of IsK in cellular response to cholinergic stimulation in mouse pancreatic acini. Pflugers Arch 439:403, 2000. (Abstract) 10. ) M Kottgen, A. Hoefer, SJ Kim, U. Beschomer, R. Schreiber, MJ Hug5 and R. Greger. Carbachol activates a K+ channel of very small conductance in the basolateral membrane of rat pancreatic acinar cells. Pflugers Arch 438:597- 603, 1999. 11.) G5gelein, Heinz; Briiggemann, Andrea; Gerlach, Uwe; Brendel, Joachim; Busch, Andreas E. Inhibition of IKs channels by HMR 1556. Naunyn-Schmiedeberg's Arch. Pharmacol. (2000), 362(6 ), 480-488